PROJECT SUMMARY/ABSTRACT Despite significant research advances in the past two decades, Alzheimer?s disease (AD) remains the sixth leading cause of death that cannot be prevented, cured or even slowed. Compelling evidence indicates that early events in AD are triggered by synaptic dysfunction resulting in memory deficits associated with AD clinical manifestation. However, the mechanism leading to synapse dysfunction associated memory deficits remains elusive thus impeding successful therapeutic intervention. Bridging this critical gap in our current knowledge is the goal of this proposal. We present compelling preliminary results that support our hypothesis that phospholipase D1 (PLD1) contributes to the detrimental impact on synapses and subsequent cognitive deficits. We will test our central hypothesis by pursuing the following specific aim: testing whether synaptic PLD1 levels/signaling are elevated through epigenetic regulation in the CNS of AD patients as a function of disease severity and cognitive decline. The present project is highly significant because the proposed studies will establish PLD1 as a key player in synaptic dysfunction and associated cognitive deficits. The successful completion of the aims will provide insight into the involved molecular mechanisms and therapeutic possibilities using small molecule inhibitors for PLD1 in preventing memory deficits associated with AD clinical progression. The proposed project will improve our scientific understanding of how synaptic dysfunction is mediated by PLD1 and its associated signaling partners in contributing to synaptic vulnerability.